Intraglomerular Proteinase Activity in Adriamycin-lnduced Nephropathy

Abstract

Adriamycin (ADR)-induced nephropathy is characterized by focal and segmental glomerulosclerosis and is supposed to be an ideal model of chronic progressive renal disease. The aim of our study was to investigate whether there might be an altered activity of glomerular proteinases in ADR nephropathy, thereby aggravating glomerular protein accumulation as an important initiating hallmark of glomerulosclerosis. In fact, we could demonstrate significantly enhanced levels of intraglomerular protein and DNA content in the experimental animals at week 7, 12 and 22 after administration of ADR. When relating intraglomerular proteinase activity, which was measured in ultrasonically destroyed isolated glomeruli, obtained by differential sieving techniques, to the intraglomerular protein and DNA content, this enzyme activity was significantly reduced throughout the observation period. Based on these data, we suggest that this relatively decreased proteinase activity in glomeruli exposed to ADR might play a pathogenetic role in the development of glomerular hypertrophy, an important harbinger of glomerulosclerosis.

Effects of Adriamycin on the Balance of Glomerular Protein Metabolism: Studies in Isolated Glomeruli of the Atlantic Hagfish, <i>Myxine glutinos</i><i>a</i>

“…In accordance with the suggestion of an ADR-impaired proteolytic degradation, glomerular protein accumulation has recently also been assigned to a diminished proteolytic activity in glomeruli of ADRtreated rats [3]. ADR, either directly or me diated by reactive oxygen species, interferes with proteolytic activities by both changing the substrate protein or the enzyme itself.…”

“…Previous studies proved that alterations in the glomerular metabolic balance, such as in creased protein synthesis [1,2] and/or dimin ished proteolytic activities [3,4] with a con comitant enrichment of protein into the glo merulus, play an important role during the development of glomerulopathies.…”

“…Therefore, the metabolism of the glomerulus is of impor tance if the causes and effects of glomerular diseases are to be better understood. Altera tions in the glomerular protein metabolism as an increased protein synthesis [1,2] and/or diminished proteolytic activities [3,4] with a concomitant enrichment of protein into the glomerulus have previously been associated with various renal disease.…”

Prkdc participates in mitochondrial genome maintenance and prevents Adriamycin-induced nephropathy in mice

“…Proposed mechanisms of ADR-induced tissue damage include introduction of double-stranded DNA breaks (DSBs), lipid peroxidation, inhibition of protease activity, disruption of the cytoskeletal and extracellular matrix, and inhibition of the topoisomerase II-mediated religation of the broken DNA strands (13)(14)(15)(16). In addition, mutations in mitochondrial DNA (mtDNA) and reduction in mtDNA copy number have been increasingly identified as major contributors to ADR-induced tissue injury: ADR can damage mtDNA directly, by intercalating into mtDNA, or indirectly, by generating ROS, producing mtDNA depletion in the kidney and heart after short-term treatment (17)(18)(19)(20)(21).…”

Molecular Basis of Injury and Progression in Focal Glomerulosclerosis

“…It has been suggested that there may be defective collagenolytic activity in injured glomeruli that progress to glomerulosclerosis, with a resulting imbalance between synthesis and degradation [144]. Glomeruli from Adriamycin-induced nephropathy have been shown to have decreased collagenolytic activity [153, 154]; although cultured mesangial cells from transgenic mice overexpressing growth hormone have decreased matrix metalloproteinase 9 levels, remnant glomeruli have increases in matrix metalloproteinase 2 and TIMP-1 and TIMP-2 [155], suggesting complex interactions mediating the net decreases in collagenolytic activity.…”